Migraine is a debilitating condition characterized by recurrent attacks of often severe throbbing headache, typically together with nausea and sensitivity to light and sound. Migraines are frequently preceded by a focal neurological symptom called an aura. Current standard of care for treating migraine is the use of the triptan class of drugs. However, approximately 30% of patients do not find relief from triptans. In addition, triptans are contraindicated in migraneurs with high risk for cardiovascular diseases (e.g., diabetes, obesity, and hypercholesterolemia). Thus, there remains a need for new therapeutic paradigms for the treatment of migraine.
Calcitonin gene related peptide (CGRP) is a 37 amino acid peptide, resulting from alternative splicing of the calcitonin gene. CGRP is implicated in many physiological and pathophysiological conditions. It was discovered that truncated peptides (e.g., CGRP(8-37) or CGRP(27-37)) could act as antagonists at the CGRP receptor. These peptides were useful as research tools, but such peptides were not pursued in clinical trials. Drug discovery efforts focusing on non-peptidic small molecules yielded several compounds that advanced to clinical development, such as olcegepant and telcagepant. Despite apparent effectiveness in treating migraine, these programs were all stopped, mostly due to concerns of liver toxicity. More recently, drug development efforts targeting the CGRP pathway for migraine have refocused on monoclonal antibodies against CGRP or its receptor.
The CGRP receptor is the seven transmembrane CLR (calcitonin like receptor) in complex with RAMP1 (Receptor Activity Modulating Peptide 1). In addition to CGRP receptor, CGRP also activates the adrenomedullin (AM) receptors AM1 and AM2 (CLR+RAMP2 and CLR+RAMP3, respectively) at higher concentrations. The AM receptors are thought to have an effect on reproduction; cardiovascular and kidney function; inflammation and other conditions. A selective CGRP-R antagonist with reduced activity at the AM receptors would reduce risk of adverse events due to disruption of AM signaling.